tbuckley/cabot-search huggingface dataset:
A Novel, Brief, Fully Automated Intervention to Extend the Antidepressant Effect of a Single Ketamine Infusion: A Randomized Clinical Trial
Authors: Rebecca B. Price, Crystal Spotts, Benjamin Panny, Angela Griffo, Michelle Degutis, Nicolas Cruz, Elizabeth Bell, Kevin Do-Nguyen, Meredith L. Wallace, Sanjay J. Mathew, Robert H. Howland
Journal: American Journal of Psychiatry (2022)

Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing neuroplasticity. The authors tested whether an automated, computer-based approach could efficiently leverage enhanced neuroplasticity to extend the durability of rapid clinical response.A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression were randomized in a double-blind, parallel-arm design to receive an active/active treatment combination (ketamine plus active "automated self-association training" [ASAT]; N=53) or one of two control arms that lacked either the active drug component (saline plus active ASAT; N=51) or the active behavioral component (ketamine plus sham ASAT; N=50). One day after a single infusion of intravenous ketamine (0.5 mg/kg over 40 minutes) or inert placebo (saline), active ASAT-targeting self-worth through automated "evaluative conditioning" training delivered by computer-or sham ASAT (consisting of identical computer tasks that included no positive or self-referential stimuli) was given, delivered twice daily over 4 consecutive days (eight sessions, ≤20 minutes per session). The prespecified primary outcome measure throughout the main (30-day) study period was score on the Montgomery-Åsberg Depression Rating Scale (MADRS).Ketamine rapidly and significantly reduced depression scores at 24 hours postinfusion (group-by-time interaction: standardized beta [β]=-1.30, 95% CI=-1.89, -0.70; t=-4.29, df=150). In intent-to-treat linear mixed models, depression scores in the ketamine+ASAT group remained significantly and stably low over the 30-day study period relative to those of the saline+ASAT group (β=-0.61, 95% CI=-0.95, -0.28; t=-3.62, df=148). By contrast, depression scores following ketamine+sham treatment followed a significant, increasing linear trajectory from 24 hours to 30 days, approaching the levels observed in the saline+ASAT group (group-by-time interaction relative to the saline+ASAT group: β=0.015, 95% CI=0.003, 0.03; t=2.35, df=568).After priming the brain with ketamine, training positive self-associations could provide an efficient, low-cost, portable, noninvasive, and highly dissemination-ready strategy for leveraging and extending ketamine's rapid antidepressant effects.
COVID-19 Thrombotic Complications and Therapeutic Strategies
Authors: Alexander C. Fanaroff, Renato D. Lopes
Journal: Annual Review of Medicine (2022)

Shortly after the emergence of coronavirus disease 2019 (COVID-19) in late 2019, clinicians rapidly recognized an apparent association between the disease and both arterial and venous thrombotic complications, which was confirmed in epidemiologic studies. Based on these data, hospitals empirically developed and implemented protocols with different strategies for anticoagulation of hospitalized COVID-19 patients. Subsequent randomized controlled trials (RCTs) clarified the role of anticoagulation in patients hospitalized with COVID-19 and recently discharged from the hospital. In this review, we discuss the epidemiology and pathophysiology of thrombosis in patients with COVID-19, observational comparative effectiveness analyses that provided hints of a benefit from anticoagulation, and finally the RCTs that established which patients with COVID-19 benefit from treatment-dose anticoagulation. These RCTs have demonstrated that hospitalized, noncritically ill patients with COVID-19 benefit from treatment-dose anticoagulation, but patients who are hospitalized and critically ill, discharged from the hospital, or not hospitalized do not benefit.
Anterior Insula–Associated Social Novelty Recognition: Pivotal Roles of a Local Retinoic Acid Cascade and Oxytocin Signaling
Authors: Sun-Hong Kim, Kyongman An, Ho Namkung, Atsushi Saito, Matthew D. Rannals, James R. Moore, Marina Mihaljevic, Sneha Saha, Seyun Oh, Mari A. Kondo, Koko Ishizuka, Kun Yang, Brady J. Maher, Minae Niwa, Akira Sawa
Journal: American Journal of Psychiatry (2022)

Deficits in social cognition consistently underlie functional disabilities in a wide range of psychiatric disorders. Neuroimaging studies have suggested that the anterior insula is a "common core" brain region that is impaired across neurological and psychiatric disorders, which include social cognition deficits. Nevertheless, neurobiological mechanisms of the anterior insula for social cognition remain elusive. This study aims to fill this knowledge gap.
Margin status and survival outcomes after breast cancer conservation surgery: prospectively registered systematic review and meta-analysis
Authors: James R Bundred, Sarah Michael, Beth Stuart, Ramsey I Cutress, Kerri Beckmann, Bernd Holleczek, Jane E Dahlstrom, Jacqui Gath, David Dodwell, Nigel J Bundred
Journal: BMJ (2022)

Abstract Objective To determine if margin involvement is associated with distant recurrence and to determine the required margin to minimise both local recurrence and distant recurrence in early stage invasive breast cancer. Design Prospectively registered systematic review and meta-analysis of literature. Data sources Medline (PubMed), Embase, and Proquest online databases. Unpublished data were sought from study authors. Eligibility criteria Eligible studies reported on patients undergoing breast conserving surgery (for stages I-III breast cancer), allowed an estimation of outcomes in relation to margin status, and followed up patients for a minimum of 60 months. Patients with ductal carcinoma in situ only or treated with neoadjuvant chemotherapy or by mastectomy were excluded. Where applicable, margins were categorised as tumour on ink (involved), close margins (no tumour on ink but &lt;2 mm), and negative margins (≥2 mm). Results 68 studies from 1 January 1980 to 31 December 2021, comprising 112 140 patients with breast cancer, were included. Across all studies, 9.4% (95% confidence interval 6.8% to 12.8%) of patients had involved (tumour on ink) margins and 17.8% (13.0% to 23.9%) had tumour on ink or a close margin. The rate of distant recurrence was 25.4% (14.5% to 40.6%) in patients with tumour on ink, 8.4% (4.4% to 15.5%) in patients with tumour on ink or close, and 7.4% (3.9% to 13.6%) in patients with negative margins. Compared with negative margins, tumour on ink margins were associated with increased distant recurrence (hazard ratio 2.10, 95% confidence interval 1.65 to 2.69, P&lt;0.001) and local recurrence (1.98, 1.66 to 2.36, P&lt;0.001). Close margins were associated with increased distant recurrence (1.38, 1.13 to 1.69, P&lt;0.001) and local recurrence (2.09, 1.39 to 3.13, P&lt;0.001) compared with negative margins, after adjusting for receipt of adjuvant chemotherapy and radiotherapy. In five studies published since 2010, tumour on ink margins were associated with increased distant recurrence (2.41, 1.81 to 3.21, P&lt;0.001) as were tumour on ink and close margins (1.44, 1.22 to 1.71, P&lt;0.001) compared with negative margins. Conclusions Involved or close pathological margins after breast conserving surgery for early stage, invasive breast cancer are associated with increased distant recurrence and local recurrence. Surgeons should aim to achieve a minimum clear margin of at least 1 mm. On the basis of current evidence, international guidelines should be revised. Systematic review registration CRD42021232115.
Neoadjuvant Chemotherapy Is Associated with Altered Immune Cell Infiltration and an Anti-Tumorigenic Microenvironment in Resected Pancreatic Cancer
Authors: Andressa Dias Costa, Sara A. Väyrynen, Akhil Chawla, Jinming Zhang, Juha P. Väyrynen, Mai Chan Lau, Hannah L. Williams, Chen Yuan, Vicente Morales-Oyarvide, Dalia Elganainy, Harshabad Singh, James M. Cleary, Kimberly Perez, Kimmie Ng, William Freed-Pastor, Joseph D. Mancias, Stephanie K. Dougan, Jiping Wang, Douglas A. Rubinson, Richard F. Dunne, Margaret M. Kozak, Lauren Brais, Emma Reilly, Thomas Clancy, David C. Linehan, Daniel T. Chang, Aram F. Hezel, Albert C. Koong, Andrew J. Aguirre, Brian M. Wolpin, Jonathan A. Nowak
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood. Experimental Design: We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient outcomes. Results: In the multi-institutional resection cohort, immune cells exhibited substantial heterogeneity across patient tumors and were located predominantly in stromal regions. Unsupervised clustering using immune cell densities identified four main patterns of immune cell infiltration. One pattern, seen in 20% of tumors and characterized by abundant T cells (T cell–rich) and a paucity of immunosuppressive granulocytes and macrophages, was associated with improved patient survival. Neoadjuvant chemotherapy was associated with a higher CD8:CD4 ratio, greater M1:M2–polarized macrophage ratio, and reduced CD15+ARG1+ immunosuppressive granulocyte density. Within neoadjuvant-treated tumors, 72% showed a T cell–rich pattern with low immunosuppressive granulocytes and macrophages. M1-polarized macrophages were located closer to tumor cells after neoadjuvant chemotherapy, and colocalization of M1-polarized macrophages and tumor cells was associated with greater tumor pathologic response and improved patient survival. Conclusions: Neoadjuvant chemotherapy with FOLFIRINOX shifts the PDAC immune microenvironment toward an anti-tumorigenic state associated with improved patient survival.
Understanding sex-related differences in healthcare utilisation among patients with inflammatory arthritis: a population-based study
Authors: Sanjana Tarannum, Jessica Widdifield, C Fangyun Wu, Sindhu R Johnson, Paula Rochon, Lihi Eder
Journal: Annals of the Rheumatic Diseases (2022)

Our aim was to compare patterns of musculoskeletal-related healthcare utilisation between male and female patients before and after the diagnosis of inflammatory arthritis (IA).We used Ontario administrative health data to create three inception cohorts of adult patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) diagnosed between April 2010 and March 2017. Healthcare utilisation indicators including visits to physicians, and use of musculoskeletal imaging and laboratory tests were assessed in each year for 3 years before and after diagnosis and compared between male and female patients using regression models adjusting for sociodemographic factors and comorbidities. Results were reported as ORs with 95% CIs for female patients compared with male patients.A total of 41 277 patients with RA (69% female), 8150 patients with AS (51% female) and 6446 patients with PsA (54% female) were analysed.Similar trends of sex-related differences were observed in all three cohorts. Before diagnosis, female patients were more likely to visit rheumatologists (OR 1.32-2.28) and family physicians (OR 1.03-1.15) for musculoskeletal reasons, whereas male patients were more likely to visit the emergency for musculoskeletal reasons (OR 0.76-0.87). A similar female predominance was observed regarding musculoskeletal imaging and laboratory tests before diagnosis. After diagnosis, female patients were more likely to remain in rheumatology care (OR 1.12-1.24).Female patients with IA have higher healthcare utilisation than male patients which may indicate biological differences in disease course or sociocultural differences in healthcare-seeking behaviour.
Malignant clonal evolution drives multiple myeloma cellular ecological diversity and microenvironment reprogramming
Authors: Yuanzheng Liang, Haiyan He, Weida Wang, Henan Wang, Shaowen Mo, Ruiying Fu, Xindi Liu, Qiong Song, Zhongjun Xia, Liang Wang
Journal: Molecular Cancer (2022)

Abstract Background Multiple myeloma (MM) is a heterogeneous disease with different patterns of clonal evolution and a complex tumor microenvironment, representing a challenge for clinicians and pathologists to understand and dissect the contribution and impact of polyclonality on tumor progression. Methods In this study, we established a global cell ecological landscape of the bone marrow (BM) from MM patients, combining single-cell RNA sequencing and single-molecule long-read genome sequencing data. Results The malignant mutation event was localized to the tumor cell clusters with shared mutation of ANK1 and IFITM2 in all malignant subpopulations of all MM patients. Therefore, these two variants occur in the early stage of malignant clonal origin to mediate the malignant transformation of proplasmacytes or plasmacytes to MM cells. Tumor cell stemness index score and pseudo-sequential clonal evolution analysis can be used to divide the evolution model of MM into two clonal origins: types I and IX. Notably, clonal evolution and the tumor microenvironment showed an interactive relationship, in which the evolution process is not only selected by but also reacts to the microenvironment; thus, vesicle secretion enriches immune cells with malignant-labeled mRNA for depletion. Interestingly, microenvironmental modification exhibited significant heterogeneity among patients. Conclusions This characterization of the malignant clonal evolution pattern of MM at the single-cell level provides a theoretical basis and scientific evidence for a personalized precision therapy strategy and further development of a potential new adjuvant strategy combining epigenetic agent and immune checkpoint blockade.
Elevated ganglioside GM2 activator (GM2A) in human brain tissue reduces neurite integrity and spontaneous neuronal activity
Authors: Yi-Chen Hsieh, Joseph Negri, Amy He, Richard V. Pearse, Lei Liu, Duc M. Duong, Lori B. Chibnik, David A. Bennett, Nicholas T. Seyfried, Tracy L. Young-Pearse
Journal: Molecular Neurodegeneration (2022)

Abstract Background Alzheimer’s Disease (AD) affects millions globally, but therapy development is lagging. New experimental systems that monitor neuronal functions in conditions approximating the AD brain may be beneficial for identifying new therapeutic strategies. Methods We expose cultured neurons to aqueous-soluble human brain extract from 43 individuals across a spectrum of AD pathology. Multi-electrode arrays (MEAs) and live-cell imaging were used to assess neuronal firing and neurite integrity (NI), respectively, following treatments of rat cortical neurons (MEA) and human iPSC-derived neurons (iN) with human brain extracts. Results We observe associations between spontaneous activity and Aβ42:40 levels, between neurite integrity and oligomeric Aβ, and between neurite integrity and tau levels present in the brain extracts. However, these associations with Aβ and tau do not fully account for the effects observed. Proteomic profiling of the brain extracts revealed additional candidates correlated with neuronal structure and activity. Neurotoxicity in MEA and NI assays was associated with proteins implicated in lysosomal storage disorders, while neuroprotection was associated with proteins of the WAVE regulatory complex controlling actin cytoskeleton dynamics. Elevated ganglioside GM2 activator (GM2A) associates with reductions in both NI and MEA activity, and cell-derived GM2A alone is sufficient to induce a loss of neurite integrity and a reduction in neuronal firing. Conclusions The techniques and data herein introduce a system for modeling neuronal vulnerability in response to factors in the human brain and provide insights into proteins potentially contributing to AD pathogenesis.
Emerging Therapies for the Management of Richter Transformation
Authors: Elizabeth Smyth, Toby A. Eyre, Chan Y. Cheah
Journal: Journal of Clinical Oncology (2022)

Richter transformation (RT) refers to the development of an aggressive lymphoma in patients with underlying chronic lymphocytic leukemia/small lymphocytic lymphoma. Aside from a small subgroup of patients with clonally unrelated and previously untreated chronic lymphocytic leukemia, the disease responds poorly to standard therapies and prognosis is dismal. Recent developments in the understanding of the biology of RT and the advent of several targeted agents may result in improved outcomes for these patients. The purpose of this review is to analyze recent data on the pathogenesis and treatment of RT. We reviewed studies addressing the pathophysiology of RT and analyzed the data for frontline chemoimmunotherapy and emerging targeted therapies likely to play a significant role in the future management of RT. Several biologic and clinical factors may help identify those who are unlikely to respond to conventional chemoimmunotherapy; where possible, these patients should be managed with a novel approach. Emerging therapies for the management of RT include chimeric antigen receptor T-cell therapy, noncovalent Bruton tyrosine kinase inhibitors, and T-cell-engaging bispecific antibodies. The use of less toxic and more effective targeted therapies may result in improved outcomes. Larger, prospective clinical trials are required to confirm efficacy and safety of novel agents for the management of RT, particularly when used in combination with other targeted therapies and in addition to chemoimmunotherapy regimens.
The Human Right to Water: A 20-Year Comparative Analysis of Arsenic in Rural and Carceral Drinking Water Systems in California
Authors: Jenny Rempel, Isha Ray, Ethan Hessl, Jasmine Vazin, Zehui Zhou, Shin Kim, Xuan Zhang, Chiyu Ding, Ziyi He, David Pellow, Alasdair Cohen
Journal: Environmental Health Perspectives (2022)
MRD dynamics during maintenance for improved prognostication of 1280 patients with myeloma in the TOURMALINE-MM3 and -MM4 trials
Authors: Bruno Paiva, Irene Manrique, Meletios A. Dimopoulos, Francesca Gay, Chang-Ki Min, Sonja Zweegman, Ivan Špička, Raphael Teipel, María-Victoria Mateos, Nicola Giuliani, Michele Cavo, Christine Rojas Hopkins, Weijun Fu, Kaveri Suryanarayan, Alexander Vorog, Cong Li, Bingxia Wang, Jose Estevam, Richard Labotka, Ajeeta B. Dash
Journal: Blood (2022)

Measurable residual disease (MRD) evaluation may help to guide treatment duration in multiple myeloma (MM). Paradoxically, limited longitudinal data exist on MRD during maintenance. We investigated the prognostic value of MRD dynamics in 1280 transplant-eligible and -ineligible patients from the TOURMALINE-MM3 and -MM4 randomized placebo-controlled phase 3 studies of 2-year ixazomib maintenance. MRD status at randomization showed independent prognostic value (median progression-free survival [PFS], 38.6 vs 15.6 months in MRD- vs MRD+ patients; HR, 0.47). However, MRD dynamics during maintenance provided more detailed risk stratification. A 14-month landmark analysis showed prolonged PFS in patients converting from MRD+ to MRD- status vs those with persistent MRD+ status (76.8% vs 27.6% 2-year PFS rates). Prolonged PFS was observed in patients with sustained MRD- status vs those converting from MRD- to MRD+ status (75.0% vs 34.2% 2-year PFS rates). Similar results were observed at a 28-month landmark analysis. Ixazomib maintenance vs placebo improved PFS in patients who were MRD+ at randomization (median, 18.8 vs 11.6 months; HR, 0.65) or at the 14-month landmark (median, 16.8 vs 10.6 months; HR, 0.65); no difference was observed in patients who were MRD-. This is the largest MM population undergoing yearly MRD evaluation during maintenance reported to date. We demonstrate the limited prognostic value of a single-time point MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD- status as a relevant end point during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD- status. These trials were registered at www.clinicaltrials.gov as #NCT02181413 and #NCT02312258.
Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance
Authors: Mara H. Sherman, Gregory L. Beatty
Journal: Annual Review of Pathology Mechanisms of Disease (2022)

Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. Recent advances in tissue imaging capabilities, single-cell analytics, and disease modeling have shed light on organizing principles that shape the stromal complexity of PDAC tumors. These insights into the functional and spatial dependencies that coordinate cancer cell biology and the relationships that exist between cells and extracellular matrix components present in tumors are expected to unveil therapeutic vulnerabilities. We review recent advances in the field and discuss current understandings of mechanisms by which the tumor microenvironment shapes PDAC pathogenesis and therapy resistance.
Structures of Leukotriene Biosynthetic Enzymes and Development of New Therapeutics
Authors: Jesper Z. Haeggström, Marcia E. Newcomer
Journal: The Annual Review of Pharmacology and Toxicology (2022)

Leukotrienes are potent immune-regulating lipid mediators with patho-genic roles in inflammatory and allergic diseases, particularly asthma. These autacoids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, metabolic, and tumor diseases. Biosynthesis of leukotrienes involves release and oxidative metabolism of arachidonic acid and proceeds via a set of cytosolic and integral membrane enzymes that are typically expressed by cells of the innate immune system. In activated cells, these enzymes traffic and assemble at the endoplasmic and perinuclear membrane, together comprising a biosynthetic complex. Here we describe recent advances in our molecular understanding of the protein components of the leukotriene-synthesizing enzyme machinery and also briefly touch upon the leukotriene receptors. Moreover, we discuss emerging opportunities for pharmacological intervention and development of new therapeutics.